7-azaindole-2,7-naphthyridine derivative for the treatment of tumours

ABSTRACT

The compound 4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine and pharmaceutically usable salts and/or tautomers thereof. The use of this compound for the treatment of tumours, tumour growth, tumour metastases and/or AIDS.

The invention relates to the compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine

and pharmaceutically usable salts and/or tautomers thereof.

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

It has been found that the compound according to the invention and saltsand/or tautomers thereof have very valuable pharmacological propertieswhile being well tolerated.

In particular, it exhibits a cell proliferation/cell vitality-inhibitingaction as antagonist or agonist. The compound according to the inventioncan therefore be used for the combating and/or treatment of tumours,tumour growth and/or tumour metastases.

The antiproliferative action can be tested in a proliferationassay/vitality assay.

Accordingly, the compound according to the invention or apharmaceutically acceptable salt thereof is administered for thetreatment of cancer, including solid carcinomas, such as, for example,carcinomas (for example of the lungs, pancreas, thyroid, bladder orcolon), myeloid diseases (for example myeloid leukaemia) or adenomas(for example villous colon adenoma).

The tumours furthermore include monocytic leukaemia, brain, urogenital,lymphatic system, stomach, laryngeal and lung carcinoma, including lungadenocarcinoma and small-cell lung carcinoma, pancreatic and/or breastcarcinoma.

The compound is furthermore useful in the treatment of immune deficiencyinduced by HIV-1 (Human Immunodeficiency Virus Type 1).

Cancer-like hyperproliferative diseases are to be regarded as braincancer, lung cancer, squamous epithelial cancer, bladder cancer, stomachcancer, pancreatic cancer, liver cancer, renal cancer, colorectalcancer, breast cancer, head cancer, neck cancer, oesophageal cancer,gynaecological cancer, thyroid cancer, lymphomas, chronic leukaemia andacute leukaemia. In particular, cancer-like cell growth is a diseasewhich represents a target of the present invention. The presentinvention therefore relates to the compound according to the inventionas medicament and/or medicament active compound in the treatment and/orprophylaxis of the said diseases and to the use of compound according tothe invention for the preparation of a pharmaceutical for the treatmentand/or prophylaxis of the said diseases and to a method for thetreatment of the said diseases comprising the administration of thecompound according to the invention to a patient in need of such anadministration.

It can be shown that the compound according to the invention has anantiproliferative action. The compound according to the invention isadministered to a patient having a hyperproliferative disease, forexample to inhibit tumour growth, to reduce inflammation associated witha lymphoproliferative disease, to inhibit transplant rejection orneurological damage due to tissue repair, etc. The present compound isuseful for prophylactic or therapeutic purposes. As used herein, theterm “treatment” is used to refer to both the prevention of diseases andthe treatment of pre-existing conditions. The prevention ofproliferation/vitality is achieved by administration of the compoundaccording to the invention prior to the development of overt disease,for example for preventing tumour growth. Alternatively, the compound isused for the treatment of ongoing diseases by stabilising or improvingthe clinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of a human disease.

The susceptibility of a particular cell to treatment with the compoundaccording to the invention can be determined by in vitro testing.Typically, a culture of the cell is incubated with the compoundaccording to the invention at various concentrations for a period oftime which is sufficient to allow the active agents to induce cell deathor to inhibit cell proliferation, cell vitality or migration, usuallybetween about one hour and one week. In vitro testing can be carried outusing cultivated cells from a biopsy sample. The amount of cellsremaining after the treatment are then determined.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue, while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

There are many diseases associated with deregulation of cellproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compound accordingto the invention is useful in the treatment of various conditions whereproliferation and/or migration of smooth muscle cells and/orinflammatory cells into the intimal layer of a vessel is present,resulting in restricted blood flow through that vessel, for example inthe case of neointimal occlusive lesions. Occlusive graft vasculardiseases of interest include atherosclerosis, coronary vascular diseaseafter grafting, vein graft stenosis, perianastomatic prostheticrestenosis, restenosis after angioplasty or stent placement, and thelike.

The compound according to the invention also acts as regulator,modulator or inhibitor of protein kinases, in particular of theserine/threonine kinase type, which include, inter alia,phosphoinositide-dependent kinase 1 (PDK1). The compound according tothe invention exhibits a certain action in the inhibition of theserine/threonine kinases PDK1, IKKε and TBK1, and in the case of ALK-1.

PDK1 phosphorylates and activates a sub-group of the AGC protein kinasefamily, comprising PKB, SGK, S6K and PKC isoforms. These kinases areinvolved in the PI3K signal transduction pathway and control basiccellular functions, such as survival, growth and differentiation. PDK1is thus an important regulator of diverse metabolic, proliferative andlife-sustaining effects.

The compound according to the invention also exhibits TGFβ receptor Ikinase-inhibiting properties.

A number of diseases have been associated with TGF-β1 overproduction.Inhibitors of the intracellular TGF-β signalling pathway are suitabletreatments for fibroproliferative diseases. Specifically,fibroproliferative diseases include kidney disorders associated withunregulated TGF-β activity and excessive fibrosis includingglomerulonephritis (GN), such as mesangial proliferative GN, immune GNand crescentic GN. Other renal conditions include diabetic nephropathy,renal interstitial fibrosis, renal fibrosis in transplant patientsreceiving cyclosporin, and HIV-associated nephropathy. Collagen vasculardisorders include progressive systemic sclerosis, polymyositis,sclerodermatitis, dermatomyositis, eosinophilic fasciitis, morphea, orthose associated with the occurrence of Raynaud's syndrome. Lungfibroses resulting from excessive TGF-β activity include adultrespiratory distress syndrome, idiopathic pulmonary fibrosis, andinterstitial pulmonary fibrosis often associated with autoimmunedisorders, such as systemic lupus erythematosus and sclerodermatitis,chemical contact or allergies. Another autoimmune disorder associatedwith fibroproliferative characteristics is rheumatoid arthritis.

Eye diseases associated with a fibroproliferative condition includeproliferative vitreoretinopathy occurring during retinal reattachmentsurgery, cataract extraction with intraocular lens implantation, andpost-glaucoma drainage surgery and are associated with TGF-β1overproduction.

TGF-β1, as member of the TGF-β family, is a ligand of the TGF-β receptorfamily which consists of heterodimeric proteins localised on the cellmembrane which have an extracellular receptor part and an intracellularkinase domain. Members are the type I and type II receptors; see alsoHinck FEBS Lett. 2012 http://dx.doi.org/10.1016/j.febslet.2012.05.028

For signal transduction of the ligands TGF-β1, -β2 and -β3 via theircorresponding receptors, it is known that they play a role in cell cyclearrest in epithelial and haematopoietic cells, control of mesenchymalcell proliferation and differentiation, in wound healing, production ofextracellular matrix and immune suppression, see also review by MassagueAnnu. Rev. Biochem. 1998. 67:753-91.

If TGF-β1 binds to a type II receptor, the corresponding type I receptorassociates and is phosphorylated. This complex phosphorylates areceptor-regulated Smad protein (R-Smad), which then associates withSmad4, migrates to the cell core and leads to a change in the cellbehaviour there by activation of transcription.

TGF-β type I receptor, also called ALK5 (activin receptor-like kinase 5)or TβR-I, is well documented in SwissProt under P36897, as is the typeII receptor under P37173 and ALK-1 under P37023. Smad2 and Smad3 aresignalling proteins for ALK-5, and those for ALK-1 are Smad-1, -5 and -8See also Cunha BLOOD, 30 JUN. 2011 VOLUME 117, NUMBER 26, 6999

The compound according to the invention represents a selection from WO2012/104007.

The compound according to the invention has significantly higheractivity than the structurally closest compounds from WO 2012/104007.

WO 2005/095400 A1 describes other azaindole derivatives as proteinkinase inhibitors.

WO 2008/079988 A2 describes quinazoline derivatives as PDK-1 inhibitorsfor combating cancer.

WO 2008/112217 A1 describes benzonaphthyridine derivatives as PDK1inhibitors for combating cancer.

Pyridinonyl derivatives are known from WO 2008/005457 as PDK1 inhibitorsfor combating cancer.

Pyrrolopyridine kinase modulators for combating cancer are described inWO 2008/124849.

WO 2006/106326 A1 and WO 2008/156726 A1 describe other heterocycliccompounds as PDK1 inhibitors for combating cancer.

WO 2009/054941 A1 describes pyrrolopyridine derivatives as PDK1inhibitors for combating cancer.

IKKε and TBK1 are serine/threonine kinases which are highly homologousto one another and to other IkB kinases. The two kinases play anintegral role in the innate immune system. Double-stranded RNA virusesare recognised by the Toll-like receptors 3 and 4 and the RNA helicasesRIG-I and MDA-5 and result in activation of the TRIF-TBK1/IKKε-IRF3signalling cascade, which results in a type I interferon response.

In 2007, Boehm et al. described IKKε as a novel breast cancer oncogene[J. S. Boehm et al., Cell 129, 1065-1079, 2007]. 354 kinases wereinvestigated with respect to their ability to recapitulate theRas-transforming phenotype together with an activated form of the MAPKkinase Mek. IKKε was identified here as a cooperative oncogene.

In addition, the authors were able to show that IKBKE is amplified andoverexpressed in numerous breast cancer cell lines and tumour samples.The reduction in gene expression by means of RNA interference in breastcancer cells induces apoptosis and impairs the proliferation thereof.Eddy et al. obtained similar findings in 2005, which underlines theimportance of IKKε in breast cancer diseases [S. F. Eddy et al., CancerRes. 2005; 65 (24), 11375-11383].

A protumorigenic effect of TBK1 was reported for the first time in 2006.In a screening of a gene library comprising 251,000 cDNA, Korherr et al.identified precisely three genes, TRIF, TBK1 and IRF3, which aretypically involved in the innate immune defence as proangiogenic factors[C. Korherr et al., PNAS, 103, 4240-4245, 2006]. In 2006, Chien et al.[Y. Chien et al., Cell 127, 157-170, 2006] published that TBK1−/− cellscan only be transformed to a limited extent using oncogenic Ras, whichsuggests an involvement of TBK1 in the Ras-mediated transformation.Furthermore, they were able to show that an RNAi-mediated knockdown ofTBK1 triggers apoptosis in MCF-7 and Panc-1 cells. Barbie et al.recently published that TBK1 is of essential importance in numerouscancer cell lines with mutated K-Ras, which suggests that TBK1intervention could be of therapeutic importance in corresponding tumours[D. A. Barbie et al., Nature Letters 1-5, 2009].

S. I. Cunha and K. Pietras in Blood, 117 (26), 6999-7006 (2011),describe the retardation of tumour growth by inhibition of the receptorALK1, in particular in the case of breast carcinoma and melanoma.

Diseases caused by protein kinases are characterised by anomalousactivity or hyperactivity of such protein kinases. Anomalous activityrelates to either: (1) expression in cells which do not usually expressthese protein kinases; (2) increased kinase expression, which results inundesired cell proliferation, such as cancer; (3) increased kinaseactivity, which results in undesired cell proliferation, such as cancer,and/or in hyperactivity of the corresponding protein kinases.Hyperactivity relates either to amplification of the gene which encodesfor a certain protein kinase, or the generation of an activity levelwhich can be correlated with a cell proliferation disease (i.e. theseverity of one or more symptoms of the cell proliferation diseaseincreases with increasing kinase level). The bioavailability of aprotein kinase may also be influenced by the presence or absence of aset of binding proteins of this kinase.

The most important types of cancer that can be treated using thecompound according to the invention include colorectal cancer,small-cell lung cancer, non-small-cell lung cancer, multiple myeloma aswell as renal cell carcinoma and endometrium carcinoma, particularlyalso types of cancer in which PTEN is mutated, inter alia breast cancer,prostate cancer and glioblastoma.

In addition, the compound according to the invention can be used toachieve additive or synergistic effects in certain existing cancerchemotherapies and radiotherapies and/or to restore the efficacy ofcertain existing cancer chemotherapies and radiotherapies.

The compound according to the invention is also taken to mean thehydrates and solvates of this compound, furthermore pharmaceuticallyusable derivatives.

The invention also relates to the salts, and the hydrates and solvatesof this compound. Solvate of the compound are taken to mean adductionsof inert solvent molecules onto the compounds which form owing to theirmutual attractive force. Solvate are, for example, mono- or dihydratesor alcoholates.

The invention naturally also relates to the solvates of the salts of thecompound according to the invention.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compound according to the invention and also so-calledprodrug compounds.

Prodrug derivative is taken to mean the compound according to theinvention which has been modified by means of, for example, alkyl oracyl groups, sugars or oligopeptides and which is rapidly cleaved in theorgan-ism to form the active compound according to the invention.

These also include biodegradable polymer derivatives of the compoundaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active compound which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side effects or also thereduction in the advance of a disease, condition or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention relates to the compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand salts thereof and to a process for the preparation of this compoundand to pharmaceutically usable salts and tautomers thereof,characterised in that

in a Masuda reaction a compound of the formula II

in which R¹ denotes Br or I and R² denotes an azaindole protectinggroup, is reacted with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and thepinacolyl boronate formed as intermediate is reacted, in a Suzukireaction,with a compound of the formula III

in which X denotes Cl, Br or I,to give a compound of the formula IV

in which R² denotes an azaindole protecting group,and the protecting group R² is subsequently cleaved off from thecompound of the formula IV,and/or4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine isconverted into one of its salts.

Above and below, the radicals R¹ and R² have the meanings indicated inthe case of the formulae II, II and IV, unless expressly indicatedotherwise.

R¹ denotes Br or I, preferably I.

R² denotes an azaindole protecting group, preferablytert-butyloxycarbonyl or benzenesulfonyl, particularly preferablybenzenesulfonyl.

The benzenesulfonyl protecting group may also be replaced by othersulfonyl or oxycarbonyl protecting groups known to the person skilled inthe art.

The cleavage of alkyl or arylsulfonyl groups is carried out using alkalimetal hydroxide and primary alcohols under standard conditions.

The compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand also the starting materials for the preparation thereof are, inaddition, prepared by methods known per se, as described in theliterature (for example in the standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditionswhich are known and suitable for the said reactions. Use can also bemade here of variants known per se which are not mentioned here ingreater detail.

The compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylaminecan preferably be obtained by reacting a compound of the formula II witha compound of the formula III in a sequential Masuda/Suzuki reaction.

In the compounds of the formula III, X preferably denotes Cl, Br or I.

After the reaction of the compounds of the formula II with the compoundsof the formula III, the azaindole protecting group R² is also cleavedoff.

The reaction is carried out under the conditions of a Suzuki coupling.Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between 0° and 110°, in particular between about 70° andabout 100°.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to dimethoxyethane, diglyme, methanoland/or dioxane.

Pharmaceutical Salts and Other Forms

The said compound according to the invention can be used in its finalnon-salt form. On the other hand, the present invention also encompassesthe use of this compound in the form of pharmaceutically acceptablesalts thereof, which can be derived from various organic and inorganicacids and bases by procedures known in the art. Pharmaceuticallyacceptable salt forms of the compound according to the invention are forthe most part prepared by conventional methods. The acid-addition saltscan be formed by treating the compound according to the invention withpharmaceutically acceptable organic and inorganic acids, for examplehydrogen halides, such as hydrogen chloride, hydrogen bromide orhydrogen iodide, other mineral acids and corresponding salts thereof,such as sulfate, nitrate or phosphate and the like, and alkyl- andmonoarylsulfonates, such as ethanesulfonate, toluenesulfonate andbenzenesulfonate, and other organic acids and corresponding saltsthereof, such as acetate, trifluoroacetate, tartrate, maleate,succinate, citrate, benzoate, salicylate, ascorbate and the like.Accordingly, pharmaceutically acceptable acid-addition salts of thecompound according to the invention include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

The compound of the present invention, which contains basicnitrogen-containing groups, can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of the compound according to the invention areprepared by bringing the free base form into contact with a sufficientamount of the desired acid, causing the formation of the salt in aconventional manner. The free base can be regenerated by bringing thesalt form into contact with a base and isolating the free base in aconventional manner. The free base forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free base forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active compound which comprises the compound according to theinvention in the form of one of its salts, in particular if this saltform imparts improved pharmacokinetic properties on the active compoundcompared with the free form of the active compound or any other saltform of the active compound used earlier. The pharmaceuticallyacceptable salt form of the active compound can also provide this activecompound for the first time with a desired pharmacokinetic propertywhich it did not have earlier and can even have a positive influence onthe pharmacodynamics of this active compound with respect to itstherapeutic efficacy in the body.

The invention furthermore relates to medicaments comprising4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand/or pharmaceutically usable salts and tautomers thereof, andoptionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active compound perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, ofthe compound according to the invention, depending on the conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activecompound per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active compound. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active compound with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, can likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compound according to the inventioncan also be combined with a free-flowing inert excipient and thenpressed directly to give tablets without carrying out the granulation ordry-pressing steps. A transparent or opaque protective layer consistingof a shellac sealing layer, a layer of sugar or polymer material and agloss layer of wax may be present. Dyes can be added to these coatingsin order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compound according to the invention and salts and tautomers thereofcan also be administered in the form of liposome delivery systems, suchas, for example, small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from variousphospholipids, such as, for example, cholesterol, stearylamine orphosphatidyl-cholines.

The compound according to the invention and salts and tautomers thereofcan also be delivered using monoclonal antibodies as individual carriersto which the compound molecules are coupled. The compounds can also becoupled to soluble polymers as targeted medicament carriers. Suchpolymers may encompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active compoundcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activecompound can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active compound can be formulated to givea cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active compound is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of the compound according to theinvention depends on a number of factors, including, for example, theage and weight of the animal, the precise condition that requirestreatment, and its severity, the nature of the formulation and themethod of administration, and is ultimately determined by the treatingdoctor or vet. However, an effective amount of a compound according tothe invention for the treatment of neoplastic growth, for example colonor breast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or tautomer thereof can bedetermined as the fraction of the effective amount of the compoundaccording to the invention per se. It can be assumed that similar dosesare suitable for the treatment of other conditions mentioned above.

The invention furthermore relates to medicaments comprising4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand/or pharmaceutically usable salts and tautomers thereof, and at leastone further medicament active compound.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of    4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine    and/or pharmaceutically usable salts thereof, and-   (b) an effective amount of a further medicament active compound.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of4-(2-methyl-1H-pyrrolo[2,3-b]-pyridin-3-yl)-2,7-naphthyridin-1-ylamineand/or pharmaceutically usable salts and tautomers thereof, and aneffective amount of a further medicament active compound dissolved or inlyophilised form.

Use

The present compound is suitable as pharmaceutical active compound formammals, especially for humans, in the treatment and control of cancerdiseases.

The invention furthermore relates to4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand pharmaceutically usable salts and tautomers thereof for use for thetreatment of tumours, tumour growth, tumour metastases and/or AIDS.

The invention furthermore relates to4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand pharmaceutically usable salts and tautomers thereof, for use for thetreatment of fibrosis, restenosis, HIV infection, Alzheimer's,atherosclerosis and/or for the promotion of wound healing.

The present invention encompasses the use of4-(2-methyl-1H-pyrrolo-[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand/or physiologically acceptable salts and tautomers thereof for thepreparation of a medicament for the treatment or prevention of cancer.Preferred carcinomas for the treatment originate from the group cerebralcarcinoma, urogenital tract carcinoma, carcinoma of the lymphaticsystem, stomach carcinoma, laryngeal carcinoma and lung carcinoma bowelcancer. A further group of preferred forms of cancer are monocyticleukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreaticcancer, glioblastomas and breast carcinoma.

Also encompassed is the use of4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand/or physiologically acceptable salts and tautomers thereof for thepreparation of a medicament for the treatment and/or control of atumour-induced disease in a mammal, in which to this method atherapeutically effective amount of a compound according to theinvention is administered to a sick mammal in need of such treatment.The therapeutic amount varies according to the particular disease andcan be determined by the person skilled in the art without undue effort.

Particular preference is given to the use for the treatment of adisease, where the disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thesquamous epithelium, the bladder, the stomach, the kidneys, of head andneck, the oesophagus, the cervix, the thyroid, the intestine, the liver,the brain, the prostate, the urogenital tract, the lymphatic system, thestomach, the larynx and/or the lung.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The invention furthermore relates to the use of the compound accordingto the invention for the treatment of bone pathologies, where the bonepathology originates from the group osteosarcoma, osteoarthritis andrickets.

4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylaminemay also be administered together with other well-known therapeuticagents that are selected for their particular usefulness against thecondition that is being treated.

The present compound is also suitable for combination with knownanticancer agents. These known anti-cancer agents include the following:oestrogen receptor modulators, androgen receptor modulators, retinoidreceptor modulators, cytotoxic agents, antiproliferative agents,prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIVprotease inhibitors, reverse transcriptase inhibitors and furtherangiogenesis inhibitors. The present compounds are particularly suitablefor administration at the same time as radiotherapy.

“Oestrogen receptor modulators” refers to compounds which interfere withor inhibit the binding of oestrogen to the receptor, regardless ofmechanism. Examples of oestrogen receptor modulators include, but arenot limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646.

“Androgen receptor modulators” refers to compounds which interfere withor inhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere withor inhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide and N-4-carboxyphenyl-retinamide.

“Cytotoxic agents” refers to compounds which result in cell deathprimarily through direct action on the cellular function or inhibit orinterfere with cell myosis, including alkylating agents, tumour necrosisfactors, intercalators, microtubulin inhibitors and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosylate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methylpyridine)platinum, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride,diarisidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-di-methylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin (see WO00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exobenzylidenechartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propan-amine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)-dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNP|1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxyetoposide, GL331,N-[2-(dimethylamino)-ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-amino-ethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

“Antiproliferative agents” include antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 andanti-metabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-mannohepto-pyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]-1,4-thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo-(7.4.1.0.0)tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also include monoclonal antibodies to growth factors other thanthose listed under “angiogenesis inhibitors”, such as trastuzumab, andtumour suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

The medicaments of the following table are preferably, but notexclusively, combined with4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2,7]naphthyridin-1-ylamin.

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson TetraplatinMatthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-fluorouracilFludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Idatrexate Roche)Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate Etoposide (Daiichi) Teniposideor Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma- Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-Ethyl-10- Ipsen) hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet J-107088(Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) Pixantrone(Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin(Actinomycin Amonafide antibiotics D Azonafide Doxorubicin (Adriamycin)Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin LosoxantroneDaunorubicin Bleomycin sulfate (Daunomycin) (Blenoxan) EpirubicinBleomycinic acid Therarubicin Bleomycin A Idarubicin Bleomycin BRubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) PorfiromycinGPX-100 (Gem Cyanomorpholinodoxo- Pharmaceuticals) rubicin Mitoxantron(Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel(GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (CellVincristine Therapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin(Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica)Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar)Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik)PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB (PrescientAuristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug(OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga)CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitorsLetrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi)Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias)synthase ZD-9331 (BTG) CoFactor ™ (BioKeys) inhibitors DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine Thymectacin(NewBiotics) (Paligent) Edotreotid (Novartis) Farnesyl Arglabin(NuOncology Tipifarnib (Johnson & transferase Labs) Johnson) inhibitorsIonafarnib (Schering- Perillyl alcohol (DOR Plough) BioPharma)BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) ZosuquidarTariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate acetyltransferase SAHA (Aton Pharma) (Titan)inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna Labo- CMT -3 (CollaGenex)inhibitors ratories) BMS-275291 (Celltech) Ribonucleoside Marimastat(British Bio- Tezacitabine (Aventis) reductase tech) Didox (Moleculesfor inhibitors Gallium maltolate (Titan) Health) Triapin (Vion)TNF-alpha Virulizin (Lorus Therapeu- Revimid (Celgene) agonists/ tics)antagonists CDC-394 (Celgene) Endothelin-A re- Atrasentan (Abbot) YM-598(Yamanouchi) ceptor antagonists ZD-4054 (AstraZeneca) Retinoic acid re-Fenretinide (Johnson & Alitretinoin (Ligand) ceptor agonists Johnson)LGD-1550 (Ligand) Immunomodulators Interferon Dexosome therapy Oncophage(Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian CancerAdenocarcinoma vaccine Technology) (Biomira) JSF-154 (Tragen) CTP-37(AVI BioPharma) Cancer vaccine (Intercell) JRX-2 (Immuno-Rx) Norelin(Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax vaccines(CTL MGV (Progenics) Immuno) !3-Alethin (Dovetail) Melanoma vaccine (CTLCLL-Thera (Vasogen) Immuno) p21-RAS vaccine (GemVax) Hormonal andOestrogens Prednisone antihormonal Conjugated oestrogensMethylprednisolone agents Ethynyloestradiol Prednisolonechlorotrianisene Aminoglutethimide Idenestrol LeuprolideHydroxyprogesterone Goserelin caproate Leuporelin MedroxyprogesteroneBicalutamide Testosterone Flutamide Testosterone propionate OctreotideFluoxymesterone Nilutamide Methyltestosterone Mitotan DiethylstilbestrolP-04 (Novogen) Megestrol 2-Methoxyoestradiol Tamoxifen (EntreMed)Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic Talaporfin(Light Sciences) Pd-Bacteriopheophorbide agents Theralux (Theratechnolo-(Yeda) gies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics)(Pharmacyclics) Hypericin Tyrosine kinase Imatinib (Novartis) Kahalide F(PharmaMar) inhibitors Leflunomide CEP- 701 (Cephalon) (Sugen/Pharmacia)CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib(Oncogene PKC412 (Novartis) Science) Phenoxodiol O Canertjnib (Pfizer)Trastuzumab (Genentech) Squalamine (Genaera) C225 (ImClone) SU5416(Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex)ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447(Medarex) Vatalanib (Novartis) ABX-EGF (Abgenix) PKI166 (Novartis)IMC-1C11 (ImClone) GW2016 (GlaxoSmith- Kline) EKB-509 (Wyeth) EKB-569(Wyeth) Various agents SR-27897 (CCK-A inhibi- BCX-1777 (PNP inhibitor,tor, Sanofi-Synthelabo) BioCryst) Tocladesine (cyclic AMP Ranpirnase(ribonuclease agonist, Ribapharm) stimulant, Alfacell) Alvocidib (CDKinhibitor, Galarubicin (RNA synthe- Aventis) sis inhibitor, Dong-A)CV-247 (COX-2 inhibitor, Tirapazamine (reducing Ivy Medical) agent, SRIInternational) P54 (COX-2 inhibitor, N-Acetylcysteine (reducingPhytopharm) agent, Zambon) CapCell ™ (CYP450 R-Flurbiprofen (NF-kappaBstimulant, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gal3 antagonist,3CPA (NF-kappaB GlycoGenesys) inhibitor, Active Biotech) G17DT immunogen(gas- Seocalcitol (vitamin D trin inhibitor, Aphton) receptor agonist,Leo) Efaproxiral (oxygenator, 131-I-TM-601 (DNA Allos Therapeutics)antagonist, PI-88 (heparanase inhibi- TransMolecular) tor, Progen)Eflornithin (ODC inhibitor, Tesmilifen (histamine an- ILEX Oncology)tagonist, YM BioSciences) Minodronic acid Histamine (histamine H2(osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin(IMPDH inhibi- Indisulam (p53 stimulant, tor, Ribapharm) Eisai)Cilengitide (integrin an- Aplidine (PPT inhibitor, tagonist, Merck KGaA)PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody,Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33inhibitor, Wyeth) antibody, Wyeth Ayerst) Exisulind (PDE-V inhibitor,PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461(PDE-V inhibitor, Immunol ™ (triclosan Cell Pathways) mouthwash, Endo)AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug,Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, activatorinhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant,TransMID-107 ™ ProMetic LifeSciences) (immunotoxin, KS Bortezomib(proteasome Biomedix) inhibitor, Millennium) PCK-3145 (apoptosis SRL-172(T-cell stimulant, promoter, Procyon) SR Pharma) Doranidazole (apoptosisTLK-286 (glutathione-S promoter, Pola) transferase inhibitor, Telik)CHS-828 (cytotoxic agent, PT-100 (growth factor Leo) agonist, PointTherapeu- trans-Retinic acid tics) (differentiator, NIH) Midostaurin(PKC inhibitor, MX6 (apoptosis promoter, Novartis) MAXIA) Bryostatin-1(PKC stimu- Apomine (apoptosis lant, GPC Biotech) promoter, ILEXOncology) CDA-II (apoptosis pro- Urocidine (apoptosis moter, Everlife)promoter, Bioniche) SDX-101 (apoptosis pro- Ro-31-7453 (apoptosis moter,Salmedix) promoter, La Roche) Ceflatonin (apoptosis pro- Brostallicin(apoptosis moter, ChemGenex) promoter, Pharmacia)

4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand pharmaceutically usable salts and/or tautomers thereof isparticularly preferably combined with immune modulators, preferably withanti-PDL-1 or IL-12.

The invention furthermore relates to4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand/or physiologically acceptable salts and tautomers thereof for usefor the treatment of tumours, where a therapeutically effective amountof a compound of the formula I is administered in combination with acompound from the group of the immune modulators.

The invention furthermore relates to4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand/or physiologically acceptable salts and tautomers thereof for usefor the treatment of tumours, where a therapeutically effective amountof a compound of the formula I is administered in combination withradiotherapy and a compound from the group of the immune modulators.

Evidence of the Action of Pharmacological Inhibitors on theProliferation/Vitality of Tumour Cells In Vitro 1.0 Background

In the present experiment description, the inhibition of tumour cellproliferation/tumour cell vitality by active compounds is described.

The cells are sown in a suitable cell density in microtitre plates(96-well format) and the test substances are added in the form of aconcentration series. After four further days of cultivation inserum-containing medium, the tumour cell proliferation/tumour cellvitality can be determined by means of an Alamar Blue test system.

2.0 Experimental Procedure 2.1 Cell Culture

For example commercially available colon carcinoma cell lines, ovarycell lines, prostate cell lines or breast cell lines, etc.

The cells are cultivated in medium. At intervals of several days, thecells are detached from the culture dishes with the aid of trypsinsolution and sown in suitable dilution in fresh medium. The cells arecultivated at 37° Celsius and 10% CO₂.

2.2. Sowing of the Cells

A defined number of cells (for example 2000 cells) per culture/well in avolume of 180 μl of culture medium are sown in microtitre plates (96well cell-culture plates) using a multichannel pipette. The cells aresubsequently cultivated in a CO2 incubator (37° C. and 10% CO2).

2.3. Addition of the Test Substances

The test substances are dissolved, for example, in DMSO and subsequentlyemployed in corresponding concentration (if desired in a dilutionseries) in the cell culture medium. The dilution steps can be adapteddepending on the efficiency of the active compounds and the desiredspread of the concentrations. Cell culture medium is added to the testsubstances in corresponding concentrations. The addition of the testsubstances to the cells can take place on the same day as the sowing ofthe cells. To this end, in each case 20 μl of substance solution fromthe predilution plate are added to the cultures/wells. The cells arecultivated for a further 4 days at 37° Celsius and 10% CO₂.

2.4. Measurement of the Colour Reaction

In each case, 20 μl of Alamar Blue reagent are added per well, and themicrotitre plates are incubated, for example, for a further seven hoursin a CO2 incubator (at 37° C. and 10% CO2). The plates are measured in areader with a fluorescence filter at a wavelength of 540 nm. The platescan be shaken gently immediately before the measurement.

3. Evaluation

The absorbance value of the medium control (no cells and test substancesused) is subtracted from all other absorbance values. The controls(cells without test substance) are set equal to 100 percent, and allother absorbance values are set in relation thereto (for example in % ofcontrol):

Calculation:

$\frac{100*\begin{pmatrix}{{{value}\mspace{14mu} {with}\mspace{14mu} {cells}\mspace{14mu} {and}\mspace{14mu} {test}\mspace{14mu} {substance}} -} \\{{value}\mspace{14mu} {of}\mspace{14mu} {medium}\mspace{14mu} {control}}\end{pmatrix}}{\left( {{{value}\mspace{14mu} {with}\mspace{14mu} {cells}} - {{value}\mspace{14mu} {of}\mspace{14mu} {medium}\mspace{14mu} {control}}} \right)}$

IC₅₀ values (50% inhibition) are determined with the aid of statisticsprograms, such as, for example, RS1.

4.0 Test for the Inhibition of PDK1

The experimental batches are carried out in a flashplate system with 384wells/microtitration plate.

In each case, the PDK1 sample His₆-PDK1(1-50) (3.4 nM), the PDK1substrate biotin-bA-bA-KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (400 nM),4 μM ATP (with 0.2 μCi of ³³P-ATP/well) and the test substance in 50 μlof conventional experimental solution per well are incubated at 30° C.for 60 min. The test substances are employed in correspondingconcentrations (if desired in a dilution series). The control is carriedout without test substance. The reaction is stopped using standardmethods and washed. The activity of the kinase is measured via theincorporated radioactivity in top count. In order to determine thenon-specific kinase reaction (blank value), the experimental batches arecarried out in the presence of 100 nM staurosporine.

5.0 Evaluation

The radioactivity (decompositions per minute) of the blank value (no useof test substance in the presence of staurosporine) is subtracted fromall other radioactivity values. The controls (kinase activity withouttest substance) are set equal to 100 percent and all other radioactivityvalues (after subtracting the blank value) are expressed set in relationthereto (for example in % of the control).

Calculation:

$\frac{100*\begin{pmatrix}{{{value}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {kinase}\mspace{14mu} {activity}\mspace{14mu} {with}\mspace{14mu} {test}\mspace{14mu} {substance}} -} \\{{blank}\mspace{14mu} {value}}\end{pmatrix}}{\left( {{{value}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {control}} - {{blank}\mspace{14mu} {value}}} \right)} = {\% \mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {control}}$

IC₅₀ values (50% inhibition) are determined with the aid of statisticsprogrammes, such as, for example, RS1. IC₅₀ data of compounds accordingto the invention are indicated in Table 1.

Material Order No. Manufacturer Microtitre plates for cell culture167008 Nunc (Nunclon Surface 96-well plate) DMEM P04-03550 Pan BiotechPBS (10x) Dulbecco 14200-067 Gibco 96-well plates (polypropylene) 267334Nunc AlamarBlue ™ BUF012B Serotec FCS 1302 Pan Biotech GmbH Trypsin/EDTAsolution 10x L 2153 Biochrom AG 75 cm² culture bottles 353136 BD FalconA2780 93112519 ECACC Colo205 CCL222 ATCC MCF7 HTB22 ATCC PC3 CRL-1435ATCC 384-well flash plates SMP410A001PK Perkin Elmer

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺.

IC₅₀ data of compounds according to the invention are indicated in Table1.

IKKε—Kinase Test (IKKepsilon)

The kinase assay is performed as 384-well flashplate assay. 1 nM IKKε,800 nM biotinylated IκBα (19-42) peptide(biotin-C6-C6-GLKKERLLDDRHDSGLDSMKDEE) and 10 μM ATP (with 0.3 μCi of³³P-ATP/well) are incubated in a total volume of 50 μl (10 mM MOPS, 10mM magnesium acetate, 0.1 mM EGTA, 1 mM dithiothreitol, 0.02% of Brij35,0.1% of BSA, 0.1% of BioStab, pH 7.5) with or without test substance at30° C. for 120 min. The reaction is stopped using 25 μl of 200 mM EDTAsolution, filtered off with suction after 30 min at room temperature,and the wells are washed 3 times with 100 μl of 0.9% NaCl solution. Thenon-specific proportion of the kinase reaction (blank) is determinedusing 3 μM EMD 1126352 (BX-795). Radioactivity is measured in theTopcount. IC₅₀ values are calculated using RS1.

TBK1—Kinase Test

The kinase assay is performed as 384-well flashplate assay.

0.6 nM TANK binding kinase (TBK1), 800 nM biotinylated MELK-derivedpeptide (biotin-Ah-Ah-AKPKGNKDYHLQTCCGSLAYRRR) and 10 μM ATP (with 0.25μCi of ³³P-ATP/well) are incubated in a total volume of 50 μl (10 mMMOPS, 10 mM magnesium acetate, 0.1 mM EGTA, 1 mM DTT, 0.02% of Brij35,0.1% of BSA, pH 7.5) with or without test substance at 30° C. for 120min. The reaction is stopped using 25 μl of 200 mM EDTA solution,filtered off with suction after 30 min at room temperature, and thewells are washed 3 times with 100 μl of 0.9% NaCl solution. Thenon-specific proportion of the kinase reaction (blank) is determinedusing 100 nM staurosporine. Radioactivity is measured in the Topcount.IC₅₀ values are calculated using RS1.

In-Vitro (Enzyme) Assay for Determination of the Efficacy of theInhibitors of the Inhibition of TGF-Beta-Mediated Effects

As an example, the ability of the inhibitors to eliminateTGF-beta-mediated growth inhibition is tested.

Cells of the lung epithelial cell line Mv1Lu are sown in a defined celldensity in a 96-well microtitre plate and cultivated overnight understandard conditions. Next day, the medium is replaced by medium whichcomprises 0.5% of FCS and 1 ng/ml of TGF-beta, and the test substancesare added in defined concentrations, generally in the form of dilutionseries with 5-fold steps. The concentration of the solvent DMSO isconstant at 0.5%. After a further two days, Crystal Violet staining ofthe cells is carried out. After extraction of the Crystal Violet fromthe fixed cells, the absorption is measured spectrophotometrically at550 nm. It can be used as a quantitative measure of the adherent cellspresent and thus of the cell proliferation during the culture.

Test for the Inhibition of ALK-5

The experimental batches are carried out in a flashplate system with 384wells/microtitre plate.

In each case, 31.2 nM of GST-ALK5, 439 nM of GST-SMAD2 and 3 mM of ATP(with 0.3 μCi of 33P-ATP/well) in a total volume of 35 μl of buffer (20mM HEPES, 10 mM MgCl2, 5 mM MnCl2, 1 mM DTT, 0.1% of BSA, pH 7.4) perwell are incubated without or with test substance at 5 to 10 differentconcentrations at 30 C for 45 min. The reaction is stopped using 25 μlof 200 mM EDTA solution and filtered off with suction after 30 min atroom temperature.

The wells are washed 3 times with 100 μl of 0.9% aqueous NaCl solution,and the residual radioactivity is measured in a TopCount instrument(Perkin-Elmer). The IC50 values are calculated using the RS1 software.

Evaluation

The radioactivity (decompositions per minute) of the blank value (no useof test substance in the presence of 100 nM staurosporine) is subtractedfrom all other radioactivity values. The controls (kinase activitywithout test substance) are set equal to 100 percent and all otherradioactivity values (after subtracting the blank value) are expressedset in relation thereto (for example in % of the control).

Calculation:

$\frac{100*\begin{pmatrix}{{{value}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {kinase}\mspace{14mu} {activity}\mspace{14mu} {with}\mspace{14mu} {test}\mspace{14mu} {substance}} -} \\{{blank}\mspace{14mu} {value}}\end{pmatrix}}{\left( {{{value}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {control}} - {{blank}\mspace{14mu} {value}}} \right)} = {\% \mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {control}}$

IC₅₀ values (concentration of the test substance at 50% inhibition) aredetermined with the aid of statistics programmes, such as, for example,RS1. IC₅₀ data of compounds according to the invention are indicated inTable 2.

Test for the Inhibition of ALK-1

The assay known to the person skilled in the art is carried out asindicated under URLhttp://www.reactionbiology.com/webapps/main/Kinases/Invitrogen100114/ALK1.pdf.

ALK1/ACVRL1

(Serine/threonine-protein kinase receptor R3, activin receptor-likekinase 1, ALK-1, TGF-B superfamily receptor type I, TSR-I, SKR3,ACVRLK1)

CAT#: ALK1 Enzyme: Human ALK1

Substrate: Casein, 20 mg/ml

ATP 10 μM Reaction:

HPLC/MS method:Column: Chromolith SpeedROD RP-18e, 50×4.6 mm²

Gradient: A:B=96:4 to 0:100

Flow rate: 2.4 ml/minEluent A: water+0.05% of formic acidEluent B: acetonitrile+0.04% of formic acid

Wavelength: 220 nm

Mass spectroscopy: positive modem.p.=melting pointMS (ESI): mass spectroscopy (electrospray ionisation)MS (EI): mass spectroscopy (electron impact ionisation)

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, depending on the constitution of the endproduct, to values between 2 and 10, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate, evaporated and purified by chromatographyon silica gel and/or by crystallisation.

Syntheses

The compound according to the invention is prepared by Pd-catalysedcross-coupling of starting material 1(4-bromo-2,7-naphthyridin-1-ylamine) with starting material 2(1-benzenesulfonyl-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine)and subsequent cleaving off of the benzenesulfonyl group using alcoholsunder basic conditions.

Starting Material 1:

4-Bromo-2,7-naphthyridin-1-ylamine, CAS 959558-28-2, is commerciallyavailable and is prepared by bromination of 2,7-naphthyridin-1-ylamineusing bromine in acetic acid.

Alternatively, the compound is prepared from 2H-2,7-naphthyridin-1-oneCAS 67988-50-5, the hydrobromide CAS 950746-19-7 or the hydrochlorideCAS 369648-60-2.

Bromination gives 4-bromo-2,7-naphthyridin-1(2H)-one CAS 959558-27-1,which is converted into 4-bromo-1-chloro-2,7-naphthyridine bychlorinating compounds, such as POCl₃ and/or PCl₅. Reaction with ammoniaor ammonia equivalents gives 2,7-naphthyridin-1-ylamine.

Alternatively, 4-methylnicotinonitrile CAS 5444-01-9 is reacted with DMFacetal (for example CAS 4637-24-5 [dimethyl]), giving4-((E)-2-dimethylamino-vinyl)nicotinonitrile CAS 36106-34-0, which iscyclised to 2,7-naphthyridin-1-ylamine.

Starting Material 2:

1-(Benzenesulfonyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineCAS 943324-08-1 is commercially available and is prepared from3-iodo-2-methyl-1-(benzenesulfonyl)-7-azaindole CAS 943324-07-0 byPd-catalysed reaction with bis(pinacolato)diboron CAS 73183-34-3(Seefeld et al., WO 2007/076423 A2, page 170).

Alternatively, the compound3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole CAS 744209-37-8 isemployed instead of 3-iodo-2-methyl-1-(benzenesulfonyl)-7-azaindole.

EXAMPLES 4-Bromo-2,7-naphthyridin-1-ylamine

940 ml of DMF dimethyl acetal are added to a solution of 200 g of4-methylnicotinonitrile in 940 g of DMF, and the mixture is heated underreflux at 120-110 for 3 days. The mixture is cooled to 35° C., pouredinto 10 litres of ice-water and cooled at 4° C. for 16 h. Theprecipitate is filtered off, washed with water and dried, giving 263 gof 4-((E)-2-dimethylaminovinyl)nicotinonitrile; M˜173.22 g/mol; M+Hfound 174, NMR corresponds.

810 g of ammonium formate are added to 253 g of4-((E)-2-dimethylaminovinyl)nicotinonitrile in a 4 litre vessel. 300 mlof AcOH are then added, and the mixture is heated at 115° C. for 20 h.The mixture is cooled, 5 litres of water are added, and the mixture isextracted 10× with 0.5 litre of CH₂Cl₂. The aqueous phase is adjusted to˜pH 10 using 160 g of NaOH. The aqueous phase is extracted with MTBether, the organic phase is separated off and dried over sodium sulfate.Removal of the solvent and drying gives 59 g of2,7-naphthyridin-1-ylamine, M˜145.16 g/mol, M+H found 146, NMRcorresponds.

32 g of 2,7-naphthyridin-1-ylamine is dissolved in 200 ml of acetic acidat room temperature. 35 g of bromine in 200 ml of acetic acid are thenadded slowly that the temperature does not exceed 25°. The mixture isstirred for a further 60 minutes.

The suspension obtained is dissolved in 500 ml of water, and the pH isadjusted to pH 7-8 using 500 ml of 25% aqueous ammonia solution.

The mixture is stirred for 14 h. The brown precipitate is filtered off,washed with water and dried, giving 28.3 g of crude product.Purification by flash chromatography in ethyl acetate/methanol gives18.5 g of 4-bromo-2,7-naphthyridin-1-ylamine, M˜224.06 g/mol, M+H found224.

1-(Benzenesulfonyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

4.8 ml of a 2M solution of lithium diisopropylamine in THF/heptane areadded dropwise over the course of 60 min. to a solution of 1 g of1-(benzenesulfonyl)-7-azaindole in 20 ml of THF at −70° C. under an N₂atmosphere. The mixture is allowed to warm to 20° over the course of 50minutes. The suspension is cooled to −70°, and a solution of 1.1, g ofiodomethane in 20 ml of THF is added dropwise over the course of 20minutes. The mixture is stirred at −70° for one hour and subsequently atroom temperature for 14 h. The mixture is diluted with water andextracted with dichloromethane. The extract is dried over sodiumsulfate, filtered, the solvent is removed and crystallised fromcyclohexane, giving 0.68 g of 2-methyl-1-(benzenesulfonyl)-7-azaindole,M˜272.32 g/mol, M+H found 273, NMR corresponds.

Bromination in DMF:

25 g of NBS in 75 ml of DMF are added to a solution of 34.8 g of2-methyl-1-(benzenesulfonyl)-7-azaindole in 75 ml of DMF. The mixture isstirred at room temperature for 1 h, poured into water, the precipitatewhich has precipitated out is separated off, washed with water anddried, giving 42 g of 3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole,M˜351.22 g/mol, M+H found 351.

Bromination in Acetonitrile:

72 mg of NBS in 2 ml of CH₃CN are added to a solution of 100 mg of2-methyl-1-(benzenesulfonyl)-7-azaindole in 3 ml of CH₃CN. The mixtureis stirred at room temperature for 20 h, poured into water, theprecipitate which has precipitated out is separated off and dried,giving 93 mg of 3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole,M˜351.22 g/mol, M+H found 351.

2.6 g of potassium acetate and 300 mg of PdCl₂(PPh₃)₂ are added to asolution of 3 g of 3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole and2.9 g of bispinacolatodiboron in 30 ml of diethylene glycol dimethylether. The mixture is heated at 120° for 3 h, diluted with water andextracted with ethyl acetate. The organic phase is dried over sodiumsulfate, filtered off, and the solvent is removed, giving 3 g of1-(benzenesulfonyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine,M˜398.29 g/mol, M+H found 399.

4-(1-Benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine

23.7 g of tripotassium phosphate and 3.2 g oftrans-dichlorobis(tricyclohexyl-phosphine)palladium(II) are added to asolution of 12.5 g of 4-bromo-2,7-naphthyridin-1-ylamine in 400 ml ofdiglyme and 15 ml of water. The mixture is heated to 125°, and 25 g of1-(benzenesulfonyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinein 100 ml of diglyme are added dropwise over the course of 30 minutes.The mixture is stirred at 125° for 3 h, at room temperature for 20 h andthe solvent is subsequently removed and the mixture is subjected toconventional work-up. The product is purified by means of flashchromatography over 330 g of silica with a methanol gradient in ethylacetate with 200 ml/min with UV detection at 254 nm, giving a purefraction (5.1 g) and a contaminated fraction (6.5 g) of4-(1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine,M˜415.47 g/mol, M+H found 416.

4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine

A mixture of 23 g of4-(1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamineand 26 g of caesium carbonate in 400 ml of THF/trifluoroethanol (1:1vol) is heated under reflux for 20 h. The mixture is cooled, the solventis removed, and the product is purified by means of flash chromatographyover 220 g of silica with a methanol gradient in ethyl acetate with 150ml/min with UV detection at 254 nm, giving 12.2 g of4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine,M˜275.31, M+H found 276.2;

¹H NMR (500 MHz, DMSO-d₆) ppm [ppm] 11.75 (s, 1H), 9.64-9.57 (m, 1H),8.50 (d, J=5.8, 1H), 8.15 (dd, J=4.7, 1.5, 1H), 7.98 (s, 1H), 7.42 (dd,J=7.8, 1.6, 1H), 7.31 (s, 2H), 7.18 (dd, J=5.8, 0.9, 1H), 6.97 (dd,J=7.8, 4.7, 1H), 2.29 (s, 3H).

TABLE 2 Inhibition of TGF-beta kinase ALK5 and ALK1 Comparison of thecompound according to the invention with compounds from the prior artIC₅₀ [nM] [TGF-beta] IC₅₀ [nM] enzym. [TGF-beta] IC₅₀ [nM] Compound No.Structure ALK5 cell. [ALK1] “A32” from WO 2012/104007

43 770 n.d “A24” from WO 2012/104007

13  72 n.d. “A13” from WO 2012/104007

16 160 200 4-(2-Methyl-1H- pyrrolo[2,3-b]- pyridin-3-yl)-2,7-naphthyridin-1-yl- amine

  4.6  28  79

The following examples relate to medicaments:

Example A Injection Vials

A solution of 100 g of the compound according to the invention and 5 gof disodium hydrogenphosphate in 3 l of bidistilled water is adjusted topH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activecompound.

Example B Suppositories

A mixture of 20 g of the compound according to the invention with 100 gof soya lecithin and 1400 g of cocoa butter is melted, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activecompound.

Example C Solution

A solution is prepared from 1 g of the compound according to theinvention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D Ointment

500 mg of the compound according to the invention are mixed with 99.5 gof Vaseline under aseptic conditions.

Example E Tablets

A mixture of 1 kg of the compound according to the invention, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active compound.

Example F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G Capsules

2 kg of the compound according to the invention are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active compound.

Example H Ampoules

A solution of 1 kg of the compound according to the invention in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active compound.

1. The compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine

or a pharmaceutically acceptable salt or tautomer thereof.
 2. Apharmaceutical composition comprising4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine ora pharmaceutically acceptable salt or tautomer thereof according toclaim 1, and one or more pharmaceutically acceptable excipients and/oradjuvants.
 3. A method for treating a tumour, tumour growth, tumourmetastases or AIDS, comprising administering to a subject in needthereof an effective amount of the compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine ora pharmaceutically acceptable salt or tautomer thereof according toclaim
 1. 4. A method for treating a tumour, comprising administering toa subject in need thereof an effective amount of the compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine ora pharmaceutically acceptable salt or tautomer thereof according toclaim 1 in combination with a compound selected from the groupconsisting of 1) oestrogen receptor modulator, 2) androgen receptormodulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5)antiproliferative agent, 6) prenyl-protein-transferase inhibitor, 7)HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reversetranscriptase inhibitor and 10) further angiogenesis inhibitors.
 5. Amethod for treating a tumour, comprising administering to a subject inneed thereof an effective amount of the compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine ora pharmaceutically acceptable salt or tautomer thereof according toclaim 1 in combination with radiotherapy and a compound selected fromthe group consisting of 1) oestrogen receptor modulator, 2) androgenreceptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent,5) antiproliferative agent, 6) prenyl-protein transferase inhibitor, 7)HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reversetranscriptase inhibitor and 10) further angiogenesis inhibitors.
 6. Amethod for treating a tumour, comprising administering to a subject inneed thereof an effective amount of the compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine ora pharmaceutically acceptable salt or tautomer thereof according toclaim 1 in combination with an immune modulator compound.
 7. A methodfor treating a tumour, comprising administering to a subject in needthereof an effective amount of the compound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine ora pharmaceutically acceptable salt or tautomer thereof according toclaim 1 in combination with radiotherapy and an immune modulatorcompound.
 8. A method for treating a tumour, tumour growth, tumourmetastases or AIDS, wherein prevention is excluded, comprisingadministering to a subject in need thereof an effective amount of thecompound4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-1-ylamine ora pharmaceutically acceptable salt or tautomer according to claim 1.